Adding Lesinurad May Lower Uric Acid

Combined with febuxostat, the drug beat out monotherapy in gout patients.

Co-administration of lesinurad, an investigational selective uric acid reabsorption inhibitor, and febuxostat was superior to either agent alone in lowering serum uric acid (sUA) in patients with gout and hyperuricemia, according to results from a phase Ib study.

"Once daily administration of lesinurad 400 and 600 mg in combination with either 40 or 80 mg/day doses of febuxostat achieved sUA-lowering effects that were significantly more pronounced than either dose of single-agent febuxostat in gout patients with high baseline sUA levels (58 mg/dL),"according to Roy Fleischmann, MD, of Metroplex Clinical Research Center in Dallas, and colleagues.

The finding is consistent with the superiority of other combinations (i.e., allopurinol and benzbromarone) in lowering sUA levels compared with monotherapy, they wrote.

As they report in Rheumatology, 20 of 21 adults enrolled with gout and a screening serum uric acid level of at least 8 mg/dL completed the two-center, open-label, multiple-dose study, designed to evaluate the pharmacodynamics, pharmacokinetics, and safety of lesinurad combined with febuxostat.

Participants were assigned to either 40 mg/day (group 1; n=12) or 80 mg/day (group 2; n=9) of febuxostat. After 1 week of febuxostat monotherapy, lesinurad was added at a dosage of 400 mg/day for 1 week, increased to 600 mg/day for a second week.

Colchicine, 0.6 mg/day, was given to prevent gout flares from 14 days prior to the first dose of febuxostat (or 7 days prior to the first dose of febuxostat for subjects not washing out from urate-lowering therapy) until 7 days after the last dose of febuxostat or the combination of febuxostat and lesinurad.

Either dosage of lesinurad when added to febuxostat led to a greater decline from baseline in serum urate concentrations compared with febuxostat alone. Decreases in sUA levels were significantly greater at all time points (P<0.05) for both combination treatment groups compared with febuxostat monotherapy. All patients receiving combination therapy achieved serum uric acid levels less than 6 mg/dL at 24 hours post-dose compared with 56% to 67% with febuxostat alone, irrespective of dose. Further, the combination resulted in 100% of patients achieving sUA levels less than 5 mg/dL at 6 hours post-dose and 82% at 24 hours post-dose, which was superior to febuxostat monotherapy at either dosage.

"These results are potentially clinically significant and could translate into improved outcomes for patients, especially those with tophaceous gout, in whom the lower the sUA levels achieved, the faster the reduction in tophaceous deposits," the authors wrote.

The fractional excretion of urate (FEUA) increased by 83% to 124% across all combination treatments after 7 days compared with baseline. Increases in FEUA were greater with combination treatments at both dosages of lesinurad compared with febuxostat alone at both dosage level. The 400- and 600-mg/day dosages of lesinurad in combination with either febuxostat dosage were equally effective at increasing the FEUA in urine from baseline.

Mean urate renal clearance was also improved by adding lesinurad to febuxostat. Urate renal clearance over a 24-hour interval increased by 62% to 184% across all combinations after 7 days compared with baseline.

These changes did not result in mean concentrations of urine uric acid greater than 10mg/dL, "suggesting little to no increased risk of urate stone formation with the combinations studied," the authors note.

Combining lesinurad and febuxostat did not result in any clinically meaningful pharmacokinetic changes of either drug. Colchicine pharmacokinetics were unaffected by febuxostat but peak plasma exposure decreased by about 20% and total plasma exposure decreased by about 30% to 35% with lesinurad co-administration.

Twelve treatment-emergent adverse events were reported in group 1 and 15 in group 2, with headache (four patients in each group) and gout flare (three patients in group 1 and five patients in group 2) being the most frequent. No serious adverse events occurred and no patient discontinued as a result of an adverse event.

The unblinded nature of the study represents a limitation.

"This is a potentially very useful strategy to attain control of hyperuricemia in patients with refractory gout. Although a major contributor to refractory hyperuricemia is the apparent reluctance of clinicians to appropriately titrate urate-lowering therapies, the dramatic efficacy of this combination in patients who did not achieve target urate levels with febuxostat, 80 mg, indicates that combination therapy is a very viable option," according to Brian Mandell, MD, PhD at the Cleveland Clinic, The long-term renal safety of a potent uricosuric agent with respect to nephrolithiasis and interstitial renal function remains to be demonstrated in large scale clinical trials, he added.

Authors report employment at and consultant fees from Ardea Biosciences USA, which supported the study, in addition to study grants from the company. Technical writing assistance for this publication was also funded by Andrea Biosciences.

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